Over the last 25 years our laboratory research on extracorporeal gas exchange and perfusion (ECMO) has progressed from oxygenator design, through the physiologic response to ECMO, through the development of extracorporeal technology to safe, simple automated systems which can be used to support cardiac or pulmonary function for days. Clinical success with ECMO indicates that expansion to total mechanical extracorporeal life support (ECLS) is feasible, but expansion of the technology requires a solution to two problems: 1) anticoagulation and thrombocytopenia, and 2) multiple organ failure. Despite many innovative approaches to anticoagulation and new prosthetic surfaces, systemic heparin anticoagulation is still required for extracorporeal circulation. A new group of anticoagulants inhibit clotting at specific early stages of the cascade. We will evaluate inhibitors of Factor IXa and Xa, used systemically or on the surface. Nitric oxide, a potent inhibitor of platelet adherence and activation, can be incorporated into the plastic materials and ventilating gas in the ECMO system, eliminating surface thrombogenesis, platelet consumption, and systemic anticoagulation without affecting endogenous platelet function. This research will develop and characterize thrombosis prevention leading to prolonged extracorporeal circulation without anticoagulation or thrombocytopenia. This will allow extension of mechanical life support from weeks to months, and initiate new approaches to ECLS. The non-thrombogenic surface combined with high blood flow and a unique albumin-based hemodiafiltration system can extend mechanical life support to liver failure and sepsis. The significance of this research is to decrease the mortality from cardiorespiratory and multiple organ failure. By studying prolonged support in experimental animals we will improve our understanding of the mechanisms and treatment of multiple organ failure.